Several lines of evidence suggest that immune dysregulation may contribute to the pathophysiologic findings seen in SCLS. First, a monoclonal gammopathy of unknown significance (MGUS) is present in a majority of SCLS cases. MGUS is a premalignant precursor to multiple myeloma (MM), in which a clonal plasma cell population secretes large amounts of monoclonal immunoglobulin (Ig, also referred to as a paraprotein) detectable in patient sera. Likewise, increased numbers of circulating CD25+ T cells and peri-capillary infiltration of CD8+ lymphocytes in skin have been noted during acute SCLS attacks. Finally, several patients with SCLS in whom MGUS evolved into frank myeloma or plasma cell leukemia experienced fewer capillary leak episodes after chemotherapy for the hematopoietic disorder. Considered together, these findings suggest that the monoclonal paraprotein from the dysregulated plasma cell population may be the direct or indirect source of the pathophysiologic findings observed, possibly through activation of T lymphocytes. We are exploring the molecular mechanisms of SCLS by examining the function of the monoclonal Ig in the development of vascular pathology in vitro. Using monoclonal Ig from SCLS patients, we will determine whether it binds to a specific cell type, target antigen (if any), and resulting effect (direct or indirect) on endothelial cells. We are also characterizing the proteome of SCLS serum, both pre- and post-attack, to determine whether specific biomarkers of acute symptoms can be identified. We have now evaluated 23 patients to the NIH clinical center under this protocol in the last 2 years. We are now the primary worldwide referral center for research on SCLS. Although the nomenclature of this disorder implies a pathogenic increase in vascular permeability, this hypothesis has not been formally tested, in part due to the rarity of the condition. We performed mechanistic studies using blood samples from 21 patients, the largest SCLS case series to date and found evidence for the pathogenic contribution of circulating angiogenic factors to the clinical symptoms of SCLS. Application of episodic SCLS sera to microvascular endothelial cells caused vascular endothelial cadherin (VE-cadherin) internalization, disruption of cell-cell addherens junctions, and actin stress fiber formation without endothelial apoptosis whereas the sera from the same subjects obtained during remission had no such effects. Levels of permeability mediators vascular endothelial growth factor (VEGF) and Angiopoietin 2 (Ang2) were significantly elevated in SCLS sera during acute episodes but not in asymptomatic periods or healthy control subjects. In a single patient experiencing a severe SCLS crisis, VEGF levels spiked at the beginning of the vascular leak phase followed by a slower rise in Ang2. Both returned to baseline as peripheral edema resolved. Our results support a model of SCLS pathogenesis in which circulating permeability mediators transiently activate endothelial retraction pathways, providing potential therapeutic targets (Ang2 and VEGF) for this highly lethal disorder.